Cytochrome P-450 is a family of isozymes that are present in most tissues of the body and are involved in the metabolism and activity of steroids, prostaglandins, leucotrienes, fatty acids, drugs and environmental chemicals. It has recently been shown that several of these isozymes turnover at different rates, but the basis for these findings is not understood. In this study we have found that during the catalytic turnover of rat liver microsomal cytochrome P-450 in vitro that a selective degradation of the isozymes occurred. Most striking were the findings of covalently bound heme fragments to apoprotein and high molecular weight derivatives of the apoproteins. We believe that this may represent the selective "tagging" of the apocytochrome P-450 by heme fragments or other cellular components that signals the catabolic enzymes to hydrolyze this group of enzymes.